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Polycystic kidney diseases (PKDs) are inherited disorders characterized by the formation of fluid filled renal cysts. Elevated cAMP levels in PKDs stimulate progressive cyst enlargement involving cell proliferation and transepithelial fluid secretion often leading to end-stage renal disease. The glycogen synthase kinase-3 (GSK3) family of protein kinases consists of GSK3alpha and GSK3beta isoforms and has a crucial role in multiple cellular signaling pathways. We previously found that GSK3beta, a regulator of cell proliferation, is also crucial for cAMP generation and vasopressin-mediated urine concentration by the kidneys. However, the role of GSK3beta in the pathogenesis of PKDs is not known. Here we found that GSK3beta expression and activity were markedly upregulated and associated with cyst-lining epithelia in the kidneys of mice and humans with PKD. Renal collecting duct-specific gene knockout of GSK3beta or pharmacological inhibition of GSK3 effectively slowed down the progression of PKD in mouse models of autosomal recessive or autosomal dominant PKD. GSK3 inactivation inhibited cAMP generation and cell proliferation resulting in reduced cyst expansion, improved renal function, and extended life span. GSK3beta inhibition also reduced pERK, c-Myc, and cyclin-D1, known mitogens in proliferation of cystic epithelial cells. Thus, GSK3beta has a novel functional role in PKD pathophysiology, and its inhibition may be therapeutically useful to slow down cyst expansion and progression of PKD.Kidney International advance online publication, 28 January 2015; doi:10.1038/ki.2014.427.

In mammals, glycogen synthase kinase 3 (GSK3) comprises GSK3alpha and GSK3beta isoforms. GSK3beta has been shown to play a role in the ability of kidneys to concentrate urine by regulating vasopressin -mediated water permeability of collecting ducts, while the role of GSK3alpha has yet to be discerned. To investigate the role of GSK3alpha in urine concentration, we compared GSK3alpha knockout mice (GSK3alphaKO) with wild type (WT) littermates. Under normal conditions the GSK3alphaKO mice had higher water intake and urine output. The GSK3alphaKO mice also showed reduced urine osmolality and aquaporin-2 levels, but higher urinary vasopressin. When water deprived, they failed to concentrate their urine to the same level as WT littermates. Addition of 1-desamino-8--arginine vasopressin (dDAVP) to isolated IMCD increased the cAMP response in WT mice, but this response was reduced in GSK3alphaKO mice, suggesting reduced responsiveness to vasopressin. Gene silencing of GSK3alpha in mpkCCD cells also reduced forskolin-induced aquaporin-2 expression. When treated with LiCl, an isoform non-selective inhibitor of GSK3, and known inducer of polyuria, WT mice developed significant polyuria within 6 days. However, in the GSK3alphaKO mice, the polyuric response was markedly reduced. These studies demonstrate for the first time that GSK3alpha could play a crucial role in renal urine concentration and suggest that GSK3alpha might be one of the initial targets of Li+ in LiCl -induced nephrogenic diabetes insipidus.

Glycogen synthase kinase-3 (GSK-3) is one of the few signaling molecules that regulate a truly astonishing number of critical intracellular signaling pathways. It has been implicated in several diseases including heart failure, bipolar disorder, diabetes mellitus, Alzheimer disease, aging, inflammation, and cancer. Furthermore, a recent clinical trial has validated the feasibility of targeting GSK-3 with small molecule inhibitors for human diseases. In the current review, we will focus on its expanding role in the heart, concentrating primarily on recent studies that have used cardiomyocyte- and fibroblast-specific conditional gene deletion in mouse models. We will highlight the role of the GSK-3 isoforms in various pathological conditions including myocardial aging, ischemic injury, myocardial fibrosis, and cardiomyocyte proliferation. We will discuss our recent findings that deletion of GSK-3alpha specifically in cardiomyocytes attenuates ventricular remodeling and cardiac dysfunction after myocardial infarction by limiting scar expansion and promoting cardiomyocyte proliferation. The recent emergence of GSK-3beta as a regulator of myocardial fibrosis will also be discussed. We will review our recent findings that specific deletion of GSK-3beta in cardiac fibroblasts leads to fibrogenesis, left ventricular dysfunction, and excessive scarring in the ischemic heart. Finally, we will examine the underlying mechanisms that drive the aberrant myocardial fibrosis in the models in which GSK-3beta is specifically deleted in cardiac fibroblasts. We will summarize these recent results and offer explanations, whenever possible, and hypotheses when not. For these studies we will rely heavily on our models and those of others to reconcile some of the apparent inconsistencies in the literature.

For those that view cellular signaling as a tangled mass of cooked spaghetti, a guidebook that introduces shared principles, highlights typical behaviors, and provides clear examples of the uses for these critical pathways should be invaluable. This book provides all of that and more. But it also, perhaps inadvertently, highlights overly reductionist concepts of cellular control. Hopefully, this tome will close the book on that mode of thought and stimulate a new generation to think about and understand how cellular regulation is so tightly integratedŚbecause this is the key to more effective treatments for disease.
//stke.sciencemag.org/lookup/reprint/sigtrans/7/347/pe25?ijkey=2Xv0AbaXg8ugw&keytype=ref&siteid=sigtrans>Reprint; //stke.sciencemag.org/cgi/content/full/sigtrans/7/347/pe25?ijkey=2Xv0AbaXg8ugw&keytype=ref&siteid=sigtrans>Full Text